Tenofovir disoproxil fumarate (TDF) salt is a compound having the chemical name of 9-[2-(R)-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinoyl]methoxy]propyl]adenine fumaric acid (1:1), is a prodrug to be hydrolyzed upon absorption, and is a phosphonomethoxy nucleotide analogue useful in the treatment of HIV-1 infection and chronic hepatitis B.
TDF was approved as a therapeutic agent for the treatment of AIDS, and was then approved as a therapeutic agent for the treatment of hepatitis B by the U.S. Food and Drug Administration. Tenofovir, which is an active metabolite of TDF, has a high ability to inhibit hepatitis B virus DNA in patients resistant to lamivudine (Zeffix), and is an antiviral agent belonging to Pregnancy category B (which are drugs found to have no fetal risk in animal studies) for assessment of the risk of fetal injury due to the pharmaceutical, as categorized by the U.S. Food and Drug Administration (FDA).
However, ensuring the physicochemical stability of tenofovir is known to be difficult. As reported in published literature (Pharmaceutical Research, 2001, 18, 234-237; Pharmaceutical Research, 2000, 17, 1098-1103), tenofovir disoproxil is hydrolyzed in the presence of water to give formaldehyde, which is then subjected to a condensation reaction with the N6-amine group of tenofovir disoproxil, thus producing a tenofovir disoproxil dimer as an impurity.
Generally, in order to expect consistent effects of medicines, the amount of an active ingredient has to be prevented from decomposition not only immediately after the manufacture of medicines but also during the storage thereof, and furthermore, an increase in the amounts of impurities or related substances, which are degradation products of the active ingredient during the same periods, has to be inhibited. Hence, preventing impurities from being incorporated into medicines is regarded as very important in terms of quality control of medicines.
As for the official compendium regulations of individual countries on purity testing, the Korean Pharmacopoeia has a separate regulation for related substances under the purity test section, and the U.S. Pharmacopoeia has regulations for “ordinary impurities”, in which the sum of related substances is set to 2.0% or less unless otherwise specified, or in which the amounts of related substances are regulated based on related compounds and chromatographic purity under each article of pharmaceutical drugs. Furthermore, the European and British Pharmacopoeias regulate related substances, and the Japanese Pharmacopoeia regulates related substances and amounts thereof in purity testing.
Therefore, the present inventors have studied novel salts able to minimize the generation of related substances even upon long-term storage and maximize solubility while exhibiting physicochemical properties equal or superior to those of conventional tenofovir disoproxil fumarate salt, leading to the development of novel tenofovir disoproxil edisylate salt using edisylate.